An unanswered question is the exact targeting mechanism for internalization and/or degradation of cadherins not associated with p120. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation. Candidates include presenilin-1 (Baki et al., 2001; Marambaud et al., 2002) and Hakai (Fujita et al., 2002), which are reported to compete with p120 for binding the cadherin juxtamembrane domain. Presenilin-1 binding promotes proteolytic degradation of E-cadherin (Baki et al., 2001; Marambaud et al., 2002), whereas Hakai is a ubiquitin ligase that binds tyrosine-phosphorylated E-cadherin, leading to its ubiquitination and destruction (Fujita et al., 2002). Several tyrosine kinase receptors are turned over via a similar mechanism involving the oncogene and ubiquitin ligase Cbl, which binds tyrosine-phosphorylated residues via its classical SH2 domain (for review see Hicke, 1999). However, we were unable to block E-cadherin destruction in the p120 siRNA cell lines with either presenilin or tyrosine kinase inhibitors (unpublished data). Moreover, the mechanism we describe is common to several cadherins, whereas the
